2-(4 - (diphenyl-2-pyrimidinyl)phenoxy) lower aliphatic monocarbocyclic acids and esters

ABSTRACT

THIS INVENTION RELATES TO DERIVATIVES OF ALKPHATIC ACIDS, E.G. 2-(4&#39;&#39;,6&#39;&#39;-DIPHENYL-2-PYRIMIDINYL)PHENOXY)LOWER ALIPHATIC MONOCARBOCYCLIC ACIDS AND THE CORRESPONDING LOWER ALKYL ESTERS. COMPOUNDS ARE USEFUL AS HYPOLIPIDEMICS.

United States Patent 3,558,626 2-[4 (DIPHENYL-2-PYRlMlDINYL)PHENOXY] LOWER ALIPHATIC MONOCARBOCYCLIC ACIDS AND ESTERS Rudolf G. Griot, Florham Park, N.J., assignor to Sandoz- Wander, Inc., Hanover, N.J., a corporation of Delaware No Drawing. Filed July 8, 1968, Ser. No. 743,002

Int. Cl. C07d 51/36 US. Cl. 260-251 7 Claims ABSTRACT OF THE DISCLOSURE This invention relates to derivatives of aliphatic acids, e.g. 2-[4-(4',6-diphenyl-2-pyrimidinyl) phenoxy1lower aliphatic monocarbocyclic acids and the corresponding lower alkyl esters. Compounds are useful as hypolipidemics.

wherein A and B are dissimilar and represent phenyl or the radical each of R and R independently represents hydrogen or straight chain lower alkyl preferably containing from 1 to 4 carbon atoms, i.e., methyl, ethyl, propyl and butyl; and

R represents hydrogen or straight or banched chain lower alkyl preferably containing from 1 to 4 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl or butyl.

The invention thus includes compounds of formulae Patented Jan. 26, 1971 wherein R R 2 and (R have the above significance.

The compounds of Formula I are most conveniently prepared by reacting an alkali-metal salt of 4-(2',6-diphenyl-4-pyrimidinyl)phenol or 4 (4,6-diphenyl-4-py rimidinyl)phenol With an appropriate Z-halo substituted aliphatic acid or ester as illustrated by the following reaction schemes:

wherein R 'R and [R are as defined, X represents halogen having an atomic weight of from to 127, i.e., chloro, bromo and iodo, and M represents an alkali-metal preferably sodium or potassium.

The above process is conveniently carried out in an inert organic solvent and at elevated temperatures. Preferably the reaction is carried out at a temperature of from about 20 C. to about 130 C. and in the same solvent employed for the preparation of the alkali-metal salt derivative of Formula II from the corresponding phenol discussed in further detail hereinafter. The resulting products (I) are readily recovered in conventional manner.

It will be readily appreciated by one skilled in the art that the compounds of Formula I wherein R is hydrogen, i.e., the free acids, may also be obtained from the corresponding esters of Formula I (i.e., where R is alkyl) by simple basic hydrolysis of the ester in conventional manner. The hydrolysis is conveniently carried out by treating the ester with an alcoholic solution of an alkalimetal hydroxide, e.g., potassium hydroxide in methanol.

Various of the 2-halo substituted alkanoic acids and esters of Formula III employed in the above-illustrated process are known and can be prepared by methods described in the literature. Such others which may not be specifically described in the literature can be prepared from available material in analogous manner.

Compounds 11a and IIb are conveniently prepared by reacting the corresponding phenols with an alkali-metal hydride, e.g., sodium hydride or potassium hydride, at room temperature (2025 C.) in an inert substantially anhydrous organic solvent. Suitable solvents include dimethylacetamide, diethylacetamide and dimethylformamide. As previously indicated hereinabove the solvent employed in preparing the phenolate is preferably employed in carrying out the subsequent reaction of the phenolate IIa or IIb with the appropriate 2-halo substituted alkanoic acid or ester (III). The preparation of the phenols 11a and Ilb are described in Examples 1 and 3. These phenols are new and form part of the present invention.

The compounds of Formula I are useful because they possess pharmacological activity in animals. In particular, the compounds are useful as hypolipidemic agents having hypocholesteremic and/ or hypotriglyceridemic activity, as indicated by tests on a group of white rats which are given -50 mg. per kg. of body weight per diem of the compound orally, for six days, followed by extraction with isopropanol of serum or plasma after anesthetizing the rats with sodium hexabarbital, and then noting the cholesterol and triglyceride contents as compared to those of a control group. The cholesterol and triglyceride contents are determined by the methods described by Lofiand, H. 3., Anal. Biochem. 9: 393 (1964), (Technicon method N 24a); and Kessler, G., and Lederer, H., Technicon Symposium, Mediad Inc., New York, pages 345-347 (1965), respectively. For such usage, the compounds may be administered orally as such or admixed with conventional pharmaceutical carriers. The dosage administered may vary depending on the particular compound employed, the therapy desired and the severity of the condition being treated. In general, satisfactory results are obtained when administered at a daily dosage of from about 4 milligrams to about 30 milligrams per kilogram of animal body weight, preferably given in divided doses, 2 to 4 times a day, or in sustained release form. For most mammals the total daily dosage is from about 0.05 gram to about 0.4 gram of the compound, and the dosage forms suitable for internal use comprise from about 12.5 milligrams to about 200 milligrams of active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

For above usages, oral administration with carriers may take place in such conventional forms as tablets, dispersible powders, granules, capsules, syrups and elixirs. Such compositions may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents, and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutical excipients, e.g., inert diluents such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and tale. The tablets may be uncoated or coated by known techniques to delay disintegration and adsorption in the gastro-intestinal tract and thereby provide a sustained action over a longer period.

Similarly, suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate), wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate) and preservatives (ethyl-p-hydroxybenzoate). Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin. The preferred pharmaceutical compositions from the standpoint of preparation and ease of administration are solid compositions, particularly hardfilled capsules and tablets.

The compounds of Formula I wherein R is hydrogen (i.e., free acids) may be similarly administered in the form of their non-toxic pharmaceutically acceptable salts. Such salts do not materially differ from the free acid forms in their pharmacological effect and are included within the scope of the invention. As illustrative of such salts there may be included aluminum salt; non-toxic alkali metal salts, e.g., potassium and sodium salts; nontoxic alkaline earth metal salts, e.g., magnesium and calcium salts; salts with N-containing bases such as ammonium salts and pharmaceutically acceptable primary, secondary and tertiary amine salts, e.g., ethanol amine salts, diethanol amine salts, and the like. Such salts are prepared in conventional manner.

A representative formulation is a tablet prepared by conventional tabletting techniques and containing the following ingredients:

Ingredient: Weight (mg) 2-methyl-[4-(2',6-diphenyl 4 pyrimidinyl) phenoxy]pr0pionic acid 50 Tragacanth 10 Lactose 197.5 Corn starch 25 Talcum 15 Magnesium stearate 2.5

The following examples show representative compounds encompassed within the scope of this invention and the manner in which such compounds are prepared. However, it is to be understood that the examples are for purposes of illustration only and are not intended as in any way limiting the scope of the invention which is defined in the appended claims.

EXAMPLE 1 2-methyl-2- [4- 4',6'-diphenyl-2'-pyrimidinyl phenoxy] propionic acid ethyl ester Step A: Preparation of 2-(4-hydroxyphenyl)-4,6-diphenylpyrimidine.200 ml. of a 15% solution of potassium t-butylate in t-butanol are added to a stirred mixture of 20.8 g. chalcone and 17.3 g. 4-hydroxybenzamidine-hydrochloride in ml. t-butanol at 30 C., and the whole mixture refluxed for 2 hours. The solvent is then evaporated in vacuo and the remainder acidified with acetic acid. The product is extracted from the aqueous phase twice, each time with 200 ml. of ethyl acetate, the organic phase Washed twice, each time with 100 ml. of water, dried over magnesium sulfate and the solvent evaporated. The crude title compound thus obtained is purified by crystallization from a suitable solvent.

Step B: Preparation of 2-methyl-2-[4-(4',6-diphenyl- 2'-pyrimidinyl)phenoxy]propionic acid ethyl ester.To 4.8 g. of sodium hydride (50% suspension in mineral oil) suspended in 200 ml. of dry dimethylacetamide is added portionwise with stirring and at room temperature 31.9 g. of 2-(4-hydroxyphenyl)-4,6-diphenylpyrimidine. To the resulting mixture is added 20 g. of ethyl bromoisobutyrate and the mixture heated at 100 C. on a water bath for 24 hours. The solvent is then evaporated in vacuo and the residue taken up in 200 ml. of diethyl ether. The ether solution is then washed first with 200 m1. of water, then with 200 ml. of a saturated aqueous sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. The ether is then evaporated off to obtain 2-methyl-2-[4-(4',6-diphenyl-2-pyrimidinyl)phenoxy]propionic acid ethyl ester.

EXAMPLE 2 2-methyl-2- [4- (4,6'-diphenyl-2'-pyrimidinyl phenoxy] propionic acid A mixture of 9 g. of 2-methyl-2-[4-(4',6'-diphenyl-2'- pyrimidinyl)phenoxy]propionic acid ethyl ester, 2.0 g. of potassium hydroxide and 40 ml. of methanol is allowed to stand at room temperature for 3 days. The solvent is then evaporated in vacuo and the residue dissolved in water. The resulting solution is extracted twice with 50 ml. (each) of diethyl ether, and the combined ether extracts then acidified with 20 ml. of 2 N hydrochloric acid and extracted three times with 50 ml. (each) of a saturated aqueous sodium chloride solution. The organic phase is then dried over anhydrous magnesium sulfate and the solvent evaporated to obtain 2-methyl-2-( [4-(4,6'-diphenyl- 2-pyrimidinyl)phenoxy]propionic acid.

What is claimed is:

1. A compound of formula wherein A and B are dissimilar and represent phenyl or the radical wherein 2. A compound of claim 1 which is wherein each of R and R independently represents hydrogen or straight chain lower alkyl and represents hydrogen or straight or branched chain lower alkyl, or when R represents hydrogen, the pharmaceutically acceptable salts thereof. 3. A compound of claim 1 which is I R1 O+-COOR3 Ra wherein each of R and R independently represents hydrogen or straight chain lower alkyl and R represents hydrogen or straight or branched chain lower alkyl or, when R represents hydrogen, the pharmaceutically acceptable salts thereof.

4. A compound of claim 1 which is 2-methyl-2-[4-(2', 6'-diphenyl-4-pyrimidinyl)phenoxylpropionic acid ethyl ester.

5-. A compound of claim 1 which is 2-methy1-2- [4-(4, 6-diphenyl-2-pyrimidinyl)phenoxylpropionic acid ethyl ester.

6. A compound of claim 1 which is 2-methyl-2-[4-(2,6- diphenyl-4-pyrimidinyl)phenoxy]-propionic acid or a pharmaceutically acceptable salt thereof.

7. A compound of claim 1 which is 2-methyl-2-[4-(4,6- diphenyl-Z-pyrimidinyl)phenoxy]-propionic acid or a pharmacetically acceptable salt thereof- References Cited UNITED STATES PATENTS 3,442,898 5/1969 Luethi 260-251 NICHOLAS S. RIZZO, Primary Examiner R. V. RUSH, Assistant Examiner US. Cl. X.R. 424-251 

